The prostaglandin E2 (PGE2), a known metabolite of the arachidonic acid cascade, is known to have a range of effects including cytoprotection, uterine contraction, lowering of the threshold of pain, promotion of peristalsis in the digestive tract, wakefulness, inhibition of stomach acid secretion, hypotensive effect, and diuretic effect.
Recent studies have found that there are subtypes of PGE2 receptors with different roles. To date, four broad subtypes are known, and these are called EP1, EP2, EP3, and EP4 (Journal of Lipid Mediators and Cell Signalling, Vol. 12, p. 379-391, 1995).
In these subtypes, the EP4 receptor is thought to be involved in inhibition of MCP-1 production from macrophages, inhibition of TNF-α, IL-2, and IFN-γ production from lymphocytes. This subtype is also believed to have involvement in anti-inflammation by enhanced IL-10 production, vasodilatation, angiogenesis, inhibition of elastic fiber formation, and regulation of MMP-9 expression. Other possible involvement of the EP4 receptor includes immune control in cancer viamyeloidderived suppressor cells, regulatory T cells, and natural killer cells.
It is therefore thought that compounds that strongly bind to the EP4 receptor, and show antagonistic activity are useful for the prevention and/or treatment of diseases caused by EP4 receptor activation, including, for example, a bone disease, a cancer, a systemic granulomatous disease, an immune disease, allergy, atopy, asthma, alveolar pyorrhea, gingivitis, periodontitis, Alzheimer's, Kawasaki disease, burn, multiple organ failure, chronic headache, pain, vasculitis, venous incompetence, varicose veins, aneurysm, aortic aneurysm, anal fistula, diabetes insipidus, stress, endometriosis, uterine adenomyosis, patent ductus arteriosus in neonates, and cholelithiasis (Pharmacological Reviews, Vol. 65, p. 1010-1052, July, 2013; 105th Annual Meeting of American Association for Cancer Research (AACR), Abstract: LB-265, Title of Presentation: ONO-AE3-208 Inhibits Myeloid Derived Suppressor Cells and Glioma Growth, Date of Presentation: Apr. 8, 2014; FEBS Letters, Vol. 364, p. 339-341, 1995; Cancer Science, Vol. 105, p. 1142-1151, 2014; Cancer Research, Vol. 70, p. 1606-1615, 2010; and Cancer Research, Vol. 62, p. 28-32, 2002).
WO02000/020371 describes a compound of the following general formula (A) used for the treatment of diseases involving prostaglandin E receptors, for example, such as pain, inflammation, and cancer.
In the general formula (A),
Ar1a is an aryl or a heteroaryl group optionally substituted with R1a or R3a, wherein R1a is CN, NO2, CON(R5a)2, or the like;
Wa represents a three- to six-membered linking group containing 0 to 2 heteroatoms selected from O, N, and S, wherein the linking group optionally contains CO, S(O)na, C═C, or an acetylene group;
Ar2a is an aryl or a heteroaryl group optionally substituted with R3a, wherein R3a is halogen, CN, or the like;
Xa is a linker attached to Ar2a at the position ortho to the bonding site for Wa; and
Qa is COOH or the like
(These are only a part of the definitions of the groups.)
WO2003/016254 describes a compound of the following general formula (B) that binds to the PGE2 receptor, particularly EP3 and/or EP4, and has antagonistic activity, useful for the prevention and/or treatment of diseases such as pain, and cancer.
In the general formula (B),
R1b represents —COOH or the like;
Ab represents (i) a single bond, (ii) C1-6 alkylene, (iii) C2-6 alkenylene, (iv) C2-6 alkynylene, or the like;
the ring Bb represents a C3-12 monocyclic or bicyclic carbon ring, or a three- to twelve-membered monocyclic or bicyclic heterocyclic ring;
R2b represents nitro, cyano, or the like;
Qb represents C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl substituted with 1 to 3 halogen atoms, cyano, nitro, or the like;
Db is a one- or two-membered linking chain of atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the linking chain may contain a double bond or a triple bond, and may be substituted with one to four R40b, wherein R40b represents an oxo, halogen, or the like; and
R3b represents (1) C1-6 alkyl, or (2) a C3-15 monocyclic, bicyclic, or tricyclic carbon ring that is substituted with one to five R42b, or that is unsubstituted, or a three- to fifteen-membered monocyclic, bicyclic, or tricyclic heterocyclic ring, wherein R42b represents C1-6 alkyl, C1-6 alkoxy, halogen, cyano, —NR46bCOR47b, or Cyc10b. (These are only a part of the definitions of the groups.)
WO1999/047497 describes a compound of the following general formula (C) used for the treatment of diseases involving prostaglandin E receptors, for example, such as pain, inflammation, and cancer.
In the general formula (C),
HETc represents a five- to twelve-membered monocyclic or bicyclic aromatic ring system having 0 to 3 heteroatoms selected from O, S(O)nc, and N(O)mc, wherein mc is 0 or 1, and nc is 0, 1, or 2;
Ac is one- or two-atom moiety and is selected from the group including —Wc— and —C(O)—, wherein Wc is O, S(O)nc, or NR17c;
Xc represents a five- to ten-membered monocyclic or bicyclic aryl or heteroaryl group having 1 to 3 heteroatoms selected from O, S(O)nc, and N(O)mc,
Yc represents O, S(O)nc, NR17c, a bond, or the like;
Bc is —(C(R18c)2)pc—Yc— (C(R18c)2)qc—, wherein pc and qc are independently 0 to 3;
Zc is OH, or the like; and
R1c, R2c, and R3c independently represent halogen, —CO2R9c, —CON(R6c)2, or the like.
(These are only a part of the definitions of the groups.)
None of these related art documents describe or suggest the present compound, specifically, the tricyclic spiro compound.